Four high-risk groups for pancreatic cancer, it is recommended to pay attention to early screening

Pancreatic cancer is a highly malignant digestive system tumor with a 5-year survival rate of about 10%. In China, according to statistics from the National Cancer Registry Center, the incidence of pancreatic cancer ranks 9th among all malignant tumors, and the mortality rate ranks 6th. The main reason is that China's early diagnosis rate of pancreatic cancer is still far behind the international advanced level, early screening for high-risk groups of pancreatic cancer has not yet been popularized, and there is insufficient awareness of screening.

To this end, the Pancreatic Disease Collaboration Group of the Chinese Society of Digestive Endoscopy took the lead in organizing domestic experts in the field of pancreatic diseases, and the Department of Gastroenterology of Drum Tower Hospital Affiliated to Nanjing University Medical School established a consensus drafting group to draft and revise the consensus opinions, and finally jointly formulated the "Chinese Consensus on Early Screening and Monitoring of High-risk Populations for Pancreatic Cancer (2021, Nanjing)". This article will introduce the target population for early screening of pancreatic cancer.

1. Individuals at high risk of hereditary pancreatic cancer

Individuals at high risk of hereditary pancreatic cancer refer to individuals with a family history of pancreatic cancer or individuals who have been confirmed to carry a pancreatic cancer susceptibility gene (mutation carrier). If at least two first-degree relatives in a family are diagnosed with pancreatic cancer, the family is considered to have a family history of pancreatic cancer.

The risk of pancreatic cancer for individuals in a family with a family history of pancreatic cancer is directly related to the number of first-degree relatives with pancreatic cancer. The risk of cancer for an individual with one first-degree relative with pancreatic cancer is 4 to 6 times that of the general population. When the number of first-degree relatives with cancer reaches 3, the individual's risk of cancer increases to 17 to 32 times that of the general population. As the age of onset of pancreatic cancer in the family decreases, the risk may increase further. Individuals at high risk of familial pancreatic cancer are at risk of pancreatic cancer throughout their lives. Therefore, early screening for pancreatic cancer is recommended for individuals with a family history of pancreatic cancer.

The risk of pancreatic cancer in patients with Peutz-Jeghers syndrome (STK11 gene mutation carriers) is 132 times that of the general population, and they are diagnosed with pancreatic cancer at a younger age (average age of onset is 40.8 years old). The risk of pancreatic cancer in carriers of CDKN2A gene mutations is 13 to 39 times that of the general population.

Long-term follow-up results of high-risk individuals for pancreatic cancer showed that the diagnosis rate of pancreatic cancer was high among confirmed high-risk gene mutation carriers, among which the incidence rate was higher in patients with Peutz-Jeghers syndrome (2/9) and CDKN2A gene mutation carriers (7%, 7/96). This consensus recommends that all patients with Peutz-Jeghers syndrome (STK11 gene mutation carriers) and CDKN2A gene mutation carriers undergo early screening for pancreatic cancer, regardless of whether the patient has a family history of pancreatic cancer.

2. Newly diagnosed diabetic patients

There is currently no authoritative definition of new-onset diabetes. Combining the published high-quality literature, this consensus defines new-onset diabetes as diabetes diagnosed within 24 months with no previous history of diabetes. More and more studies have shown that new-onset diabetes is a clinical manifestation of asymptomatic pancreatic cancer. Studies have found that patients with new-onset diabetes aged ≥50 years are considered to be at high risk for sporadic pancreatic cancer, and 0.85% of new-onset diabetes patients over 50 years old will be diagnosed with pancreatic cancer within 3 years.

In 2020, a multidisciplinary consensus in Italy on the early prediction of pancreatic cancer in patients with new-onset diabetes pointed out that people who are aged >50 years when diagnosed with diabetes, have a low body mass index and/or unexplained weight loss, high fasting blood sugar levels or difficult to control blood sugar are at higher risk of pancreatic cancer.

The new-onset diabetes enrichment model for pancreatic cancer, which is constructed based on a scoring system composed of age, weight change, blood sugar change, etc. at the time of diagnosis of new-onset diabetes, helps to identify the high-risk population for pancreatic cancer among patients with new-onset diabetes. However, there is currently no unified and complete new-onset diabetes enrichment model for pancreatic cancer, and there is no consensus on the early monitoring plan for new-onset diabetes-related pancreatic cancer.

In combination with the latest research progress at home and abroad, this consensus recommends early screening for pancreatic cancer in patients with new diabetes who are over 50 years old with a low body mass index and/or unexplained weight loss, as well as those with large short-term blood sugar fluctuations.

A prospective study followed up the high-risk population for hereditary pancreatic cancer who underwent pancreatic cancer screening. The results showed that 20% of the individuals had abnormal fasting blood glucose, and one patient was diagnosed with new-onset diabetes. If there is a family history of pancreatic cancer, a history of diabetes, and a history of smoking, the patient's risk of pancreatic cancer will increase to more than 10 times that of the healthy population. Therefore, this consensus recommends that new-onset diabetes patients in individuals at high risk of hereditary pancreatic cancer should undergo early screening for pancreatic cancer.

3. Patients with chronic pancreatitis

Chronic pancreatitis is an inflammatory process in which the pancreatic parenchyma is gradually replaced by fibrous tissue, causing irreversible changes in pancreatic function and morphology. A multicenter, retrospective study initiated by the Chronic Pancreatitis Research Group in my country found that the prevalence of chronic pancreatitis increased from 3.08/100,000 in 1996 to 13.52/100,000 in 2003.

Chronic pancreatitis in my country is mainly idiopathic (76.6%), followed by alcoholic (18.8%), abnormal pancreatic duct anatomy (2.9%), and hereditary (1.2%). The inflammation and damage caused by pancreatitis can lead to acinar duct metaplasia and gradually develop into pancreatic cancer. Therefore, chronic pancreatitis is also a risk factor for pancreatic cancer.

In 1993, a large multicenter cohort study involving 1,552 patients with chronic pancreatitis in 6 countries showed that the cumulative risk of pancreatic cancer in patients with chronic pancreatitis was 1.8% and 4.0% in 10 and 20 years, respectively. The cumulative prevalence of pancreatic cancer in patients with chronic pancreatitis in the Chinese population was 0.6%, 1.0%, and 1.3% in 3, 5, and 10 years, respectively. Therefore, chronic pancreatitis is a high-risk factor for pancreatic cancer, and patients with chronic pancreatitis should be included in early screening for pancreatic cancer.

Hereditary pancreatitis is a rare type of chronic pancreatitis, accounting for only 8.7% of non-alcoholic chronic pancreatitis, with a prevalence of (0.13-0.57)/100,000, and only 1.2% of the causes of chronic pancreatitis in China. Compared with pancreatitis caused by other causes, hereditary pancreatitis is characterized by early onset and a significantly increased risk of pancreatic cancer.

Hereditary pancreatitis is an autosomal dominant genetic disease. 65% to 100% of hereditary pancreatitis is caused by PRSS1 mutations. p.R122H and p.N29I are the more common mutation sites. The cumulative risk of cancer in PRSS1 mutation carriers 70 years after the onset of symptoms is as high as 44%. When patients with chronic pancreatitis have a family history of pancreatitis or the cause cannot be determined clinically through relevant auxiliary examinations (excluding alcoholic, biliary, hyperlipidemia, drug-related and congenital causes), hereditary pancreatitis should be highly suspected. It is recommended that patients undergo peripheral blood gene mutation testing, especially to determine whether they carry PRSS1 gene mutations.

It is reported that about 51.4% of patients with chronic pancreatitis have susceptibility gene mutations for chronic pancreatitis. In addition to PRSS1, mutations in chymotrypsin C, cystic fibrosis transmembrane conductance regulator, and serine protease inhibitor Kazal type 1 (SPINK1) are considered to be significantly associated with the early occurrence of chronic pancreatitis. In addition, carboxyl ester lipase heterozygous allele (CEL-HYB) is considered a risk factor for chronic pancreatitis, but CEL-HYB and carboxypeptidase A1 genes are not associated with the occurrence of chronic pancreatitis in Asian populations.

A prospective study based on the Chinese population showed that the risk of pancreatic cancer in patients with chronic pancreatitis carrying SPINK1 gene mutations was not increased compared with patients with chronic pancreatitis who were mutation-negative.

Based on current research, except for PRSS1, there is insufficient evidence for the association of other susceptibility genes (including SPINK1, cystic fibrosis transmembrane conductance regulator, chymotrypsin C, carboxypeptidase A1, and CEL-HYB) with pancreatic cancer.

4. Patients with pancreatic cystic tumors

With the popularization of imaging examinations, the detection rate of asymptomatic pancreatic cystic tumors has increased year by year. Compared with the general population, patients with pancreatic cystic tumors have a higher risk of pancreatic cancer, with an RR of up to 22.5 (95% confidence interval 11.0~45.3). Pancreatic cystic tumors cover a wide range, and the malignant risks of different types of pancreatic cystic tumors vary greatly. Among them, mucinous pancreatic cystic tumors are considered to have a higher risk of cancer. 15% of pancreatic cancers are believed to be caused by mucinous pancreatic cystic tumors, including mucinous neoplasms (IPMNs) and pancreatic mucinous cystadenomas (MCNs), with IPMNs accounting for the majority.

IPMN refers to a papillary tumor originating from the main pancreatic duct and/or branch pancreatic duct with a large amount of mucus secretion. According to the location and degree of involvement in the pancreas, IPMN can be divided into MD-IPMN, BD-IPMN and MT-IPMN.

It is reported that the risk of malignancy in patients with MD-IPMN and MT-IPMN is high, ranging from 38% to 68%, while the risk of malignancy in patients with BD-IPMN is relatively low, ranging from 11% to 30% in the literature. In addition, some rare pancreatic cystic tumors including solid pseudopapillary tumors (SPNs) and cystic neuroendocrine tumors (cNETs) are also considered to have potential malignancy.

Currently, there is still some controversy about the management of pancreatic cystic tumors. Relevant domestic and international guidelines recommend that patients with pancreatic cystic tumors (including MCN, SPN, cNET, IPMN) with a higher risk of canceration should undergo early screening for pancreatic cancer, multidisciplinary diagnosis and treatment discussions and elective surgical resection should be conducted for patients with MCN, SPN, cNET, MD-IPMN, and MT-IPMN, and BD-IPMN patients should be included in the screening program.

Given that it is difficult to identify the specific type of pancreatic cystic tumors and the controversy surrounding follow-up strategies for some lesions, it is recommended that once a pancreatic cystic tumor is diagnosed, the patient should be sent to a high-level pancreatic specialist center for early screening for pancreatic cancer and, if necessary, a follow-up monitoring plan should be developed after multidisciplinary discussion.

References: Pancreatic Disease Collaborative Group of the Digestive Endoscopy Branch of the Chinese Medical Association. Consensus opinion on early screening and monitoring of high-risk populations for pancreatic cancer in China (2021, Nanjing) [J]. Chinese Journal of Digestion, 2022, 42 (3): 145-157.